Expression of the vesicular glutamate transporters-1 and -2 in adult mouse dorsal root ganglia and spinal cord and their regulation by nerve injury

Brumovsky, Pablo Rodolfo; Watanabe, Masahiko; Hökfelt, Tomas

doi:10.1016/j.neuroscience.2007.02.068

Cited by 143 publications

(260 citation statements)

References 114 publications

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“…We show here that VGLUT2 is expressed in most peptidergic and nonpeptidergic (IB4 binding) C nociceptors, confirming previous studies (17)(18)(19)(20)(21)(22). With the exception of a very small number of IB4+ neurons that express VGLUT3 (Fig.…”

Section: Defining the Pain Modalities Mediated By Subsets Of Drg Neursupporting

confidence: 92%

“…S6). This finding agrees with previous deafferentation studies (17,18,23) and suggests that the weaker VGLUT2 immunoreactivity at central terminals within the dorsal horn (22) reflects less-efficient labeling and/or the requirement for only modest VGLUT2 expression for synaptic glutamate release. Together, these results indicate that VGLUT2 is, in fact, expressed by the majority of nociceptors, and that the cKO mice lack VGLUT2 in these neurons.…”

Section: Vglut2 Expressionsupporting

confidence: 91%

“…In the DRG, however, the distribution of VGLUTs remains a matter of debate. Although some studies suggest that VGLUT2 is expressed by the majority of Aδ and C nociceptors, including peptidergic and IB4-binding unmyelinated C fibers (17)(18)(19)(20)(21)(22), others found no expression of VGLUTs in these neurons (23), which questioned their glutamatergic identity (24).…”

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confidence: 99%

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VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

Scherrer

Low

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

102

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Dorsal root ganglia (DRG) neurons, including the nociceptors that detect painful thermal, mechanical, and chemical stimuli, transmit information to spinal cord neurons via glutamatergic and peptidergic neurotransmitters. However, the specific contribution of glutamate to pain generated by distinct sensory modalities or injuries is not known. Here we generated mice in which the vesicular glutamate transporter 2 (VGLUT2) is ablated selectively from DRG neurons. We report that conditional knockout (cKO) of the Slc17a6 gene encoding VGLUT2 from the great majority of nociceptors profoundly decreased VGLUT2 mRNA and protein in these neurons, and reduced firing of lamina I spinal cord neurons in response to noxious heat and mechanical stimulation. In behavioral assays, cKO mice showed decreased responsiveness to acute noxious heat, mechanical, and chemical (capsaicin) stimuli, but responded normally to cold stimulation and in the formalin test. Strikingly, although tissue injury-induced heat hyperalgesia was lost in the cKO mice, mechanical hypersensitivity developed normally. In a model of nerve injuryinduced neuropathic pain, the magnitude of heat hypersensitivity was diminished in cKO mice, but both the mechanical allodynia and the microgliosis generated by nerve injury were intact. These findings suggest that VGLUT2 expression in nociceptors is essential for normal perception of acute pain and heat hyperalgesia, and that heat and mechanical hypersensitivity induced by peripheral injury rely on distinct (VGLUT2 dependent and VGLUT2 independent, respectively) primary afferent mechanisms and pathways.nociceptor | inflammatory pain | electrophysiology | neuroanatomy P rimary afferent neurons of the dorsal root ganglia (DRG) detect a wide range of stimulus modalities and intensities (1). This is particularly true for nociceptors, which are the neurons specialized to detect noxious stimuli. Not only do subsets of nociceptors express different repertoires of neuropeptides, receptors, and ion channels, but they also project to different laminae in the spinal cord where they engage different CNS circuits (2-4). Importantly, studies in rodents in which different nociceptor populations have been deleted revealed remarkably selective behavioral deficits (e.g., heat, mechanical, or chemical pain), demonstrating the existence of behaviorally relevant peripheral-labeled lines for different modalities of pain (5-8).Whether the modality-specific contribution of sensory neurons to acute pain and to injury-induced hypersensitivity states is also manifest at the level of the different neurotransmitters expressed by these neurons is still not known. Interestingly, previous pharmacological and genetic studies that disrupted neuropeptide function did not find a modality-specific loss of pain processing (9). Here we turned our attention to glutamate, which is presumed to be released by all DRG neurons to activate second-order spinal cord neurons.Because pharmacological blockade of glutamate signaling would nonselectively inhibit the centr...

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Section: Defining the Pain Modalities Mediated By Subsets Of Drg Neursupporting

confidence: 92%

Section: Vglut2 Expressionsupporting

confidence: 91%

mentioning

confidence: 99%

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VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

Scherrer

Low

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

102

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“…Vesicular glutamate transporters (VGLUTs) sequester glutamate into synaptic vesicles and are reliable markers for glutamatergic neurons and can be used to impair glutamatergic signaling in mouse models (9)(10)(11)(12). They are expressed in mostly nonoverlapping patterns in the nervous system and in DRGs, where the expression of VGLUT1 dominates in nonnociceptive neurons, VGLUT2 in nociceptors (9), and VGLUT3 in a small subset of DRG C-low threshold mechanoreceptors (13).…”

mentioning

confidence: 99%

“…They are expressed in mostly nonoverlapping patterns in the nervous system and in DRGs, where the expression of VGLUT1 dominates in nonnociceptive neurons, VGLUT2 in nociceptors (9), and VGLUT3 in a small subset of DRG C-low threshold mechanoreceptors (13). Mice with one disrupted Vglut2 allele display intact acute pain responses, but show a reduced response to cold and mechanical stimuli after spared nerve injury (14).…”

mentioning

confidence: 99%

A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain

Lagerström

Rogóż²,

Abrahamsen³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Ablating or functionally compromising sets of sensory neurons has provided important insights into peripheral modality-specific wiring in the somatosensory system. Inflammatory hyperalgesia, cold pain, and noxious mechanosensation have all been shown to depend upon Na v 1.8-positive sensory neurons. The release of fastacting neurotransmitters, such as glutamate, and more slowly released neuropeptides, such as substance P (SP), contribute to the diversified responses to external stimuli. Here we show that deleting Vglut2 in Na v 1.8 Cre -positive neurons compromised mechanical pain and NGF-induced thermal hyperalgesia, whereas tactile-evoked sensation, thermal, formalin-evoked, and chronic neuropathic pain were normal. However, when Vglut2 f/f ;Na v 1.8 Cre mice were injected with a SP antagonist before the formalin test, the second phase pain response was nearly completely abolished, whereas in control mice, the pain response was unaffected. Our results suggest that VGLUT2-dependent signaling originating from Na v 1.8-positive neurons is a principal sensing mechanism for mechanical pain and, together with SP, inflammatory pain. These data define sets of primary afferents associated with specific modalities and provide useful genetic tools with which to analyze the pathways that are activated by functionally distinct neuronal populations and transmitters.dorsal root ganglia | mouse genetics | neuronal network | co-transmission | sensory signaling

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An Introduction to Pain and its Relation to Nervous System Disorders

Battaglia¹

2016

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Basic organisation of spinal pain pathways Primary afferent axons belonging to the somatosensory system can respond to a range of mechanical, thermal and chemical stimuli. Many of these afferents are activated by stimuli that damage (or threaten to damage) tissues, and these are known as nociceptors. Primary afferents that innervate the limbs and the trunk enter the spinal cord through the dorsal roots and form excitatory (glutamatergic) synapses with neurons in the dorsal horn. The dorsal horn contains a large number of neurons, the great majority of which have axons that arborise locally and remain in the spinal cord; these are known as interneurons and are involved in the local processing of sensory information. In addition, the dorsal horn contains projection cells-that is, neurons with axons that enter the white matter and travel rostrally to the brain. The axons of these cells are grouped into a number of different ascending tracts. The final neuronal component consists of descending axons, which originate from cells in the brain (particularly the brainstem) and terminate diffusely within the dorsal horn. Rexed (1952) divided the grey matter of the dorsal horn into six parallel laminae (numbered from dorsal to ventral), and this scheme is widely used, for example to describe the arborisation of primary afferents and the distribution of different populations of spinal neurons (Figure 1.1). The dorsal horn is somatotopically organised, the body being mapped in a bidimensional pattern onto the rostrocaudal and mediolateral axes. The other, dorsoventral dimension is arranged in a modality-specific pattern, as will be described later. Fifty years ago, Melzack and Wall (1965) proposed that neurons within the superficial dorsal horn could 'gate' the inputs from nociceptors and thus modify the perception of pain. This theory attracted a great deal of interest, and there have been numerous attempts to unravel the neuronal circuitry that underlies pain processing in the spinal cord. It turns out that this circuitry is highly complex, and we still have only a limited understanding of it. Nonetheless, it is clear that this region is very important for modulating pain in both normal and pathological states. The superficial dorsal horn is also likely to provide important targets

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Expression of the vesicular glutamate transporters-1 and -2 in adult mouse dorsal root ganglia and spinal cord and their regulation by nerve injury

Cited by 143 publications

References 114 publications

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain

An Introduction to Pain and its Relation to Nervous System Disorders

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